Sensitization of lung cancer cells to cisplatin by [beta]-elemene is mediated through blockade of cell cycle progression: antitumor efficacies of [beta]-elemene and its synthetic analogs

The development of effective agents for overcoming platinum chemoresistance in lung carcinoma continues to have high priority. We have demonstrated recently that [beta]-elemene, a novel antitumor compound, enhances cisplatin activity by triggering lung cancer cell death via apoptosis. Here, we investigated whether [beta]-elemene acts synergistically with cisplatin to inhibit non-small cell lung cancer (NSCLC) cell proliferation by blocking cell cycle progression. [beta]-Elemene substantially increased the suppressive effect of cisplatin on cell growth and proliferation in the NSCLC cell lines H460 and A549. Furthermore, [beta]-elemene augmented cisplatin in the cell cycle arrest of NSCLC cells at G^sub 2^/M. This was associated with upregulated checkpoint kinase (CHK2) expression and reduced CDC2 activity (i.e., increased phosphorylation of CDC2 on Tyr-15 and decreased phosphorylation of CDC2 on Thr-161). Moreover, [beta]-elemene and cisplatin in combination clearly decreased the protein levels of cyclin B1 and CDC25C and increased the levels of p21^sup Cip1/Waf1^, p27^sup Kip1^, and GADD45 in these cells, compared with the effects of either agent alone at the same concentration. These results suggest that the [beta]-elemene-enhanced inhibitory effect of cisplatin on lung carcinoma cell proliferation is regulated by a CHK2-mediated CDC25C/CDC2/cyclin B1 signaling pathway and leads to the blockade of cell cycle progression at G^sub 2^/M. A comparison of the cytotoxic efficacies of [beta]-elemene and three synthetic analogs ([beta]-elemenol, [beta]-elemenal, and [beta]-elemene fluoride) in the two lung cancer cell lines revealed that [beta]-elemenol and [beta]-elemene fluoride had the same antitumor efficacy as [beta]-elemene, whereas [beta]-elemenal was appreciably more potent than [beta]-elemene. Thus, although all three synthetic analogs of [beta]-elemene considerably suppressed NSCLC cell growth and proliferation, [beta]-elemenal may have greater potential as an anticancer alternative to [beta]-elemene in treating lung cancer and other tumors.[PUBLICATION ABSTRACT]